TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion.

Journal Article

Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell-cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)-induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5-enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β-induced EMT.

Full Text

Duke Authors

Cited Authors

  • Osborne, LD; Li, GZ; How, T; O'Brien, ET; Blobe, GC; Superfine, R; Mythreye, K

Published Date

  • November 2014

Published In

Volume / Issue

  • 25 / 22

Start / End Page

  • 3528 - 3540

PubMed ID

  • 25143398

Electronic International Standard Serial Number (EISSN)

  • 1939-4586

International Standard Serial Number (ISSN)

  • 1059-1524

Digital Object Identifier (DOI)

  • 10.1091/mbc.e14-05-1015

Language

  • eng